Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is the major target for antiretroviral therapy of the acquired immunodeficiency syndrome (AIDS). While some inhibitors exhibit activity against most retroviral RTs, others are specific for the HIV-1 enzyme. To develop an animal model for the therapy of the HIV-1 infection with RT inhibitors, the RT of the simian immunodeficiency virus (SIV) was replaced by the RT of HIV-1. Macaques infected with this SIV/HIV-1 hybrid virus developed AIDS-like symptoms and pathology. The HIV-1-specific RT inhibitor LY300046.HCl, but not zidovudine [3'-azido-3'-deoxythymidine (AZT)] delayed the appearance of plasma antigenemia in macaques infected with a high dose of the chimeric virus. Infection of macaques with the chimeric virus seems to be a valuable model to study the in vivo efficacy of new RT inhibitors, the emergence and reversal of drug resistance, the therapy of infections with drug-resistant viruses, and the efficacy of combination therapy.

An aided economy: the characteristics of the Transnistrian economic model. OSW Commentary No. 108, 2013-05-14

The economy of breakaway Transnistria is a peculiar combination of the command-and-distribution model inherited from the USSR with elements of a free-market economy which is heavily dependent on Russian energy and financial subsidies. The main pillars of the region’s economy are several large industrial plants, built in the Soviet era, which generate more than half of its GDP (in 2012, Transnistria’s GDP reached around US$1 billion). As a consequence, the condition of each of these companies, whose production is almost exclusively export- -oriented, has a huge impact on the economic situation in Transnistria. This makes the region extremely sensitive to any changes in the economic situation of its key trade partners. This problem is additionally aggravated by the extremely low diversification of Transnistrian exports. The only major economic entity in Transnistria which regularly yields profits and is not so heavily dependent on the external situation is Sheriff. This corporation controls the greater part of the local wholesale and retail trade, as well as a major part of the services sector on the domestic market.

Trade policy in a dynamic Heckscher-Ohlin model

The Import Substitution Process in Latin Amer ica was an attempt to enhance GDP growth and productivity by rising trade barriers upon capital-intensive products. Our main goal is to analyze how an increase in import tariff on a particular type of good affects the production choices and trade pattern of an economy. We develop an extension of the dynamic Heckscher-Ohlin model – a combination of a static two goods, two-factor Heckscher-Ohlin model and a two-sector growth model – allowing for import tariff. We then calibrate the closed economy model to the US. The results show that the economy will produce less of both consumption and investment goods under autarky for low and high levels of capital stock per worker. We also find that total GDP may be lower under free trade in comparison to autarky.

(Table 1) Age model of sediment core MD03-2705

A reconstruction of northwest African summer monsoon strength during the cold marine isotopic stage (MIS) 6 indicates a link to the seasonal migration of the Intertropical Convergence Zone (ITCZ). High-resolution studies of eolian dust supply and sea surface temperature recorded in marine core MD03-2705, on the Mauritanian margin, provide a better understanding about the penultimate glacial history of northwestern African aridity/humidity and upwelling coastal activity. Today, site MD03-2705 experiences increased upwelling and dust flux during the winter months, when the ITCZ is in a southerly position. Analyses of foraminifera isotopic composition suggest that during MIS 6.5 (180-168 ka) the average position of the ITCZ migrated north, marked by an increase in the strength of the summer monsoon, which decreased eolian dust transport and the coastal upwelling activity. The northward migration is in phase with a specific orbital combination of a low precessional index with a high obliquity signal. High-resolution analysis of stable isotopes (d18O and d13C) and microscale resolution geochemical (Ti/Al and quartz grain counts) determinations reveal that the transition between monsoonal humid (MIS 6.5) and dry (MIS 6.4) conditions has occurred in less than 1.3 ka. Such rapid changes suggest a nonlinear link between the African monsoonal rainfall system and environmental changes over the continent. This study provides new insights about the influence of vegetation and oceanic temperature feedbacks on the onset of African summer monsoon and demonstrates that, during the penultimate glacial period, changes in tropical dynamics had regional and global impacts.

Age model and ostracod countings from IODP Site 306-U1314

We present a detailed study of glacial/interglacial deep sea benthic ostracod assemblage variability at IODP Site U1314 (subpolar North Atlantic) in relation to the history of ice-rafting events and changes in deep ocean circulation over the past 170 ky. Our records of ostracod diversity, abundance and dissolution and sediment properties (IRD and CaCO3) show an excellent correspondence to high amplitude orbital and millennial variability observed in the climate records (d13C and d18O) from neighboring deep water sites, suggesting that the benthic meiofauna fluctuates synchronously with the prevailing oceanographic conditions (surface ocean conditions, deep ocean circulation and water temperature and food flux). Krithe (dominant), Argilloecia and Cytheropteron are the most abundant and diverse genera in association with Rockallia enigmatica. Three ostracod assemblages are recognized. The genera Pennyella, Argilloecia, Pelecocythere, Ambocythere, Pseudobosquetina, Bradleya and Nannocythere are associated with interglacials and interstadials, and possibly reflect increased flux of food to the sediments and more vigorous NADW formation. A transitional assemblage composed of species of Cytheropteron, Xestoleberis and Eucythere is restricted to climatic transitions and indicate moderate environmental conditions and seasonal productivity. A glacial/stadial assemblage is characterized by a temporal predominance of either intermediate-depth and shallow water Arctic/subarctic species (belonging to Cytheropteron, Polycope, Pedicythere, Swainocythere, Cluthia, Heterocyprideis, Elofsonella and Finmarchinella) or abyssal North Atlantic ostracods (Bythocythere, Dutoitella, Bathycythere and Bythocypris). The influx of high latitude taxa can be partially explained by ice-rafting, but may also represent a shift of the location of intermediate and deep water convection to the area south of Iceland. Therefore the combination of species characteristic of different watermasses during glacials may reflect shifts in the influence of high nutrient southern source water (e.g. AABW) vs. low nutrient GNAIW during glacials.

Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C

BACKGROUND: Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. METHODS: A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. RESULTS: In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. CONCLUSION: Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naive adults with CHC.

Subordinate-manager gender combination and perceived leadership style influence on emotions, self-esteem and organizational commitment

A theoretical model was developed to investigate the relationships among subordinate-manager gender combinations, perceived leadership style, experienced frustration and optimism, organization-based self-esteem and organizational commitment. The model was tested within the context of a probabilistic structural model, a discrete Bayesian network, using cross-sectional data from a global pharmaceutical company. The Bayesian network allowed forward inference to assess the relative influence of gender combination and leadership style on the emotions, self-esteem and commitment consequence variables. Further, diagnostics from backward inference were used to assess the relative influence of variables antecedent to organizational commitment. The results showed that gender combination was independent of leadership style and had a direct impact on subordinates' levels of frustration and optimism. Female manager-female subordinate had the largest probability of optimism, while male manager teamed with a male subordinate had the largest probability of frustration. Furthermore, having a female manager teamed up with a male subordinate resulted in the lowest possibility of frustration. However, the findings show that the gender issue is not simply female managers versus male managers, but is concerned with the interaction of the subordinate-manager gender combination and leadership style in a nonlinear manner. (C) 2003 Elsevier Inc. All rights reserved.

Effects of hydrogen-air non-equilibrium chemistry on the performance of a model scramjet thrust nozzle

Two aspects of hydrogen-air non-equilibrium chemistry related to scramjets are nozzle freezing and a process called 'kinetic afterburning' which involves continuation of combustion after expansion in the nozzle. These effects were investigated numerically and experimentally with a model scramjet combustion chamber and thrust nozzle combination. The overall model length was 0.5m, while precombustion Mach numbers of 3.1 +/- 0.3 and precombustion temperatures ranging from 740K to 1,400K were involved. Nozzle freezing was investigated at precombustion pressures of 190kPa and higher, and it was found that the nozzle thrusts were within 6% of values obtained from finite rate numerical calculations, which were within 7% of equilibrium calculations. When precombustion pressures of 70kPa or less were used, kinetic afterburning was found to be partly responsible for thrust production, in both the numerical calculations and the experiments. Kinetic afterburning offers a means of extending the operating Mach number range of a fixed geometry scramjet.

A simulation model of cereal-legume intercropping systems for semi-arid regions I. Model development

Cereal-legume intercropping plays an important role in subsistence food production in developing countries, especially in situations of limited water resources. Crop simulation can be used to assess risk for intercrop productivity over time and space. In this study, a simple model for intercropping was developed for cereal and legume growth and yield, under semi-arid conditions. The model is based on radiation interception and use, and incorporates a water stress factor. Total dry matter and yield are functions of photosynthetically active radiation (PAR), the fraction of radiation intercepted and radiation use efficiency (RUE). One of two PAR sub-models was used to estimate PAR from solar radiation; either PAR is 50% of solar radiation or the ratio of PAR to solar radiation (PAR/SR) is a function of the clearness index (K-T). The fraction of radiation intercepted was calculated either based on Beer's Law with crop extinction coefficients (K) from field experiments or from previous reports. RUE was calculated as a function of available soil water to a depth of 900 mm (ASW). Either the soil water balance method or the decay curve approach was used to determine ASW. Thus, two alternatives for each of three factors, i.e., PAR/SR, K and ASW, were considered, giving eight possible models (2 methods x 3 factors). The model calibration and validation were carried out with maize-bean intercropping systems using data collected in a semi-arid region (Bloemfontein, Free State, South Africa) during seven growing seasons (1996/1997-2002/2003). The combination of PAR estimated from the clearness index, a crop extinction coefficient from the field experiment and the decay curve model gave the most reasonable and acceptable result. The intercrop model developed in this study is simple, so this modelling approach can be employed to develop other cereal-legume intercrop models for semi-arid regions. (c) 2004 Elsevier B.V. All rights reserved.

Right ventricle extraction by low level and model-based algorithm

In this paper we present an algorithm as the combination of a low level morphological operation and model based Global Circular Shortest Path scheme to explore the segmentation of the Right Ventricle. Traditional morphological operations were employed to obtain the region of interest, and adjust it to generate a mask. The image cropped by the mask is then partitioned into a few overlapping regions. Global Circular Shortest Path algorithm is then applied to extract the contour from each partition. The final step is to re-assemble the partitions to create the whole contour. The technique is deemed quite reliable and robust, as this is illustrated by a very good agreement between the extracted contour and the expert manual drawing output.

Binocular interaction:Contrast matching and contrast discrimination are predicted by the same model

How do signals from the 2 eyes combine and interact? Our recent work has challenged earlier schemes in which monocular contrast signals are subject to square-law transduction followed by summation across eyes and binocular gain control. Much more successful was a new 'two-stage' model in which the initial transducer was almost linear and contrast gain control occurred both pre- and post-binocular summation. Here we extend that work by: (i) exploring the two-dimensional stimulus space (defined by left- and right-eye contrasts) more thoroughly, and (ii) performing contrast discrimination and contrast matching tasks for the same stimuli. Twenty-five base-stimuli made from 1 c/deg patches of horizontal grating, were defined by the factorial combination of 5 contrasts for the left eye (0.3-32%) with five contrasts for the right eye (0.3-32%). Other than in contrast, the gratings in the two eyes were identical. In a 2IFC discrimination task, the base-stimuli were masks (pedestals), where the contrast increment was presented to one eye only. In a matching task, the base-stimuli were standards to which observers matched the contrast of either a monocular or binocular test grating. In the model, discrimination depends on the local gradient of the observer's internal contrast-response function, while matching equates the magnitude (rather than gradient) of response to the test and standard. With all model parameters fixed by previous work, the two-stage model successfully predicted both the discrimination and the matching data and was much more successful than linear or quadratic binocular summation models. These results show that performance measures and perception (contrast discrimination and contrast matching) can be understood in the same theoretical framework for binocular contrast vision. © 2007 VSP.

Nonlinearities in the binocular combination of luminance and contrast

We studied the rules by which visual responses to luminous targets are combined across the two eyes. Previous work has found very different forms of binocular combination for targets defined by increments and by decrements of luminance, with decrement data implying a severe nonlinearity before binocular combination. We ask whether this difference is due to the luminance of the target, the luminance of the background, or the sign of the luminance excursion. We estimated the pre-binocular nonlinearity (power exponent) by fitting a computational model to ocular equibrightness matches. The severity of the nonlinearity had a monotonic dependence on the signed difference between target and background luminance. For dual targets, in which there was both a luminance increment and a luminance decrement (e.g. contrast), perception was governed largely by the decrement. The asymmetry in the nonlinearities derived from the subjective matching data made a clear prediction for visual performance: there should be more binocular summation for detecting luminance increments than for detecting luminance decrements. This prediction was confirmed by the results of a subsequent experiment. We discuss the relation between these results and luminance nonlinearities such as a logarithmic transform, as well as the involvement of contemporary model architectures of binocular vision.

Binocular combination at threshold: temporal filtering and summation of signals in separate ON and OFF channels

How does the brain combine spatio-temporal signals from the two eyes? We quantified binocular summation as the improvement in 2AFC contrast sensitivity for flickering gratings seen by two eyes compared with one. Binocular gratings in-phase showed sensitivity up to 1.8 times higher, suggesting nearly linear summation of contrasts. The binocular advantage decreased to 1.4 at lower spatial and higher temporal frequencies (0.25 cycle deg-1, 30 Hz). Dichoptic, antiphase gratings showed only a small binocular advantage, by a factor of 1.1 to 1.2, but no evidence of cancellation. We present a signal-processing model to account for the contrast-sensitivity functions and the pattern of binocular summation. It has linear sustained and transient temporal filters, nonlinear transduction, and half-wave rectification that creates ON and OFF channels. Binocular summation occurs separately within ON and OFF channels, thus explaining the phase-specific binocular advantage. The model also accounts for earlier findings on detection of brief antiphase flashes and the surprising finding that dichoptic antiphase flicker is seen as frequency-doubled (Cavonius et al, 1992 Ophthalmic and Physiological Optics 12 153 - 156). [Supported by EPSRC project GR/S74515/01].

Detection of signals corrupted by the combination of Gaussian and Non-Gaussian noise

The detection of signals in the presence of noise is one of the most basic and important problems encountered by communication engineers. Although the literature abounds with analyses of communications in Gaussian noise, relatively little work has appeared dealing with communications in non-Gaussian noise. In this thesis several digital communication systems disturbed by non-Gaussian noise are analysed. The thesis is divided into two main parts. In the first part, a filtered-Poisson impulse noise model is utilized to calulate error probability characteristics of a linear receiver operating in additive impulsive noise. Firstly the effect that non-Gaussian interference has on the performance of a receiver that has been optimized for Gaussian noise is determined. The factors affecting the choice of modulation scheme so as to minimize the deterimental effects of non-Gaussian noise are then discussed. In the second part, a new theoretical model of impulsive noise that fits well with the observed statistics of noise in radio channels below 100 MHz has been developed. This empirical noise model is applied to the detection of known signals in the presence of noise to determine the optimal receiver structure. The performance of such a detector has been assessed and is found to depend on the signal shape, the time-bandwidth product, as well as the signal-to-noise ratio. The optimal signal to minimize the probability of error of; the detector is determined. Attention is then turned to the problem of threshold detection. Detector structure, large sample performance and robustness against errors in the detector parameters are examined. Finally, estimators of such parameters as. the occurrence of an impulse and the parameters in an empirical noise model are developed for the case of an adaptive system with slowly varying conditions.

Interaction of quinolone antibiotics with the human intestinal CACO-2 cell model

The transport of a group of quinolone antibiotics across the human intestinal model, Caco-2 cells, was investigated. It was found that the transport of the quinolones generally correlated with the lipophilicity of the compounds, indicating the passive diffusional transcellular processes were involved. However, it was observed that the transport in both directions apical-to-basolateral and basolateral-to-apical was not equivalent, and polarised transport occurred. For all the quinolones studied except, BMS-284756-01, it was found that the basolateral-to-apical transport was significantly greater than the apical-to-basolateral transport. This finding suggested that the quinolones underwent a process of active secretion. The pKas and logPs for the quinolones were determined using potentiometric titrations. The measured logP values were compared with those determined using theoretical methods. The theoretical methods for calculating logP including the Moriguchi method correlated poorly with the measured logP values. Further investigations revealed that there may be an active transporter involved in the apical-to-basolateral transport of quinolones as well. This mechanism was sensitive to competing quinolones, but, it was unaffected by the metabolic inhibitor combination of sodium azide (15mM) with 2-deoxy-D-glucose (50mM). The basolateral-to-apical transport of quinolones was found to be sensitive to inhibition by a number of different inhibitors. The metabolic inhibitors, sodium azide (15mM) with 2-deoxy-D-glucose (50mM) and 2,4-dinitrophenol (1mM), were able to reduce the basolateral-to-apical transport of quinolones. A reduction in temperature from 37°C to 2°C caused an 80-fold decrease in the transport of gatifloxacin in both directions, however, this effect was not sufficient to abolish the greater basolateral-to-apical secretion. As with apical-to-basolateral transport, it was found that quinolones competed with gatifloxacin for basolateral-to-apical transport, both ofloxacin (100μM) and norfloxacin (100μM) significantly (P<0.003) decreased the basolateral-to-apical transport of gatifloxacin; however, ciprofloxacin (100μM and 300μM) had no effect. A number of inhibitors of various transport systems were also investigated. It was found that the anion transport inhibitor, probenecid (100 μM) had a significant inhibitory effect on the basolateral-to-apical transport of ciprofloxacin (P=0.039), while the cation transport inhibitor cimetidine (100μM and 500μM) had no effect. The organic anion exchange inhibitor 4,4'diisothiocyanostilbene-2-2' -disulphonic acid DIDS (400μM) also had a significant inhibitory effect (P=O.O 13). The PgP inhibitor and anion exchange inhibitor verapamil (400Mμ) was able to completely abolish the basolateral-to-apical secretion of gatifloxacin and bring it into line with the apical-to-basolateral flux. In conclusion, the apical-to-basolateral and basolateral-toapical transport of quinolones involved an active component. The basolateral-to-apical secretion was abolished by a verapamil (400μM), a bisubstrate for PgP and the anion transporter.